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| Status |
Public on Oct 10, 2024 |
| Title |
Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The liver contains a diverse array of immune cells that play distinct roles in both health and disease. However, the specific functions of these immune cells in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain poorly understood. Using a systems immunology approach, we demonstrate that reciprocal cell-cell communication operates through a dominant-subdominant pattern of ligand-receptor homeostatic pathways. In healthy controls, inflammatory immune responses predominantly function through these homeostatic pathways, indicating that the liver is not a tolerogenic organ. Chronic consumption of a Western diet (WD) altered hepatocyte function and led to interactions dominated by hepatic stellate cells (HSCs), cancer cells, and NKT cells, with 80% of NKT cells becoming the primary immune cells involved in liver homeostasis during NAFLD. In the context of HCC, 80% of all immune cell types, primarily NKT cells and monocytes, collaborated with hepatocytes and myofibroblasts to restore liver homeostasis. Dietary correction during NAFLD produced nonlinear outcomes: tumor progression was associated with the failure to maintain homeostatic immune responses, while tumor prevention correlated with sustained homeostatic immune responses predominantly driven by monocytes. These monocytes primarily targeted fibroblasts and myofibroblasts, creating a tumor-hostile microenvironment. Notably, only 5% of T cells exhibited apoptosis-inducing functions, primarily facilitating the homeostatic turnover of hepatic cells, particularly myofibroblasts and fibroblasts. Our data suggest that effective anti-tumor immune responses operate as a system through tissue homeostatic pathways that modulate the hepatic microenvironment, rather than relying solely on direct cytotoxicity against the tumor.
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| Overall design |
Eight DIAMOND mice (129A1/SvIm and C57BL/6J cross mice) were stratified into experimental groups receiving different diets at two months of age. Three mice (n=3) were on a high-fat high-sugar Western Diet (WD) for 48 weeks that developed hepatocellular carcinoma (HCC). Five mice underwent diet reversal to a standard chow diet (CD) following 36 weeks on WD, in which two mice developed HCC (n=2; RD1 and RD5), whereas 3 mice were rescued from HCC development and did not have any detectable HCC (n=3; R2, R3, and R4)
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| Contributor(s) |
Koelsch N, Mirshahi F, Aqbi HF, Seneshaw M, Idowu MO, Olex AL, Sanyal AJ, Manjili MH |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Oct 09, 2024 |
| Last update date |
Oct 11, 2024 |
| Contact name |
Nicholas J Koelsch |
| E-mail(s) |
koelschnj@vcu.edu
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| Phone |
7578183171
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| Organization name |
Virginia Commonwealth University
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| Department |
Microbiology & Immunology
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| Lab |
Manjili
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| Street address |
1810 East Cary Street Apt MG02
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| City |
Richmond |
| State/province |
Virginia |
| ZIP/Postal code |
23223 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (8)
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| GSM8561813 |
48wksmaleR3, replicate 2, snRNA-seq |
| GSM8561814 |
48wksmaleR4, replicate 3, snRNA-seq |
| GSM8561815 |
48wksmaleWD4, replicate 1, snRNA-seq |
| GSM8561816 |
48wksmaleWD5, replicate 2, snRNA-seq |
| GSM8561817 |
48wksmaleWD7, replicate 3, snRNA-seq |
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| Relations |
| BioProject |
PRJNA1170927 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE279124_RAW.tar |
392.3 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
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